Cyclopentenone Annulation of 2‐Oxocycloalkane‐1‐carbonitriles

Abstract

Phase-transfer alkylation of the 2-oxocycloalkane-I-carbonitriles l a and l b with ethyl 4-bromo-3-methoxy-2butenoate (Z), followed by deprotection and base-catalyzed cyclization gave the annulated cyclopentenones 5a and 5b, respectively, in high overall yields (Scheme 1 ) . Stereoselective catalytic hydrogenation of 5b followed by de-ethoxycarbonylation afforded 14-oxo-cis-bicyclo[l0.3.0]pentadecane-l -carbonitrile (7). Treatment of 7 with LiN(i-Pr), in THF gave the known synthetic muscone precursor 8 (Scicherrie 2). The tricycle[ 10.4.0.01~15]hexadecan-14-one (14) was prepared from 7 in 5 steps by a reaction sequence proceeding without affecting the chiral centres (Sclzemr 2). The structure of 14 was established by X-ray structure analysis (Figure).During the course of our studies on the zip reaction, we have shown that the CN group can be used as a good anion stabilizer in the ring enlargement of cycloalkanonesThe results obtained in the case of the carbon zip reaction [3] were strongly dependent on the ring size of the cycloalkanone and on the length of the alkyl-carboxylate side chain used. With this method, good yields of the C, ring enlargement were observed only for the 8-membered 0x0-carbonitrile. On the other hand, we have shown [4] that Michael adducts of 2-nitrocycloalkanones with 3-0x0-4-pentenoates rearrange smoothly into compounds enlarged by 4 C-atoms. In this case, the side chain used had a C-nucleophilic centre, twice activated by carbonyl and alkoxycarbonyl functions. Thus, it seemed reasonable to find a way for introducing a similarly activated side chain into position l of 2-oxocycloalkane-I-carbonitriles which could serve for the preparation of compounds enlarged by three C-atoms. Therefore, we decided to use ethyl 4-bromo-3-methoxy-2butenoate (2) [5] as an alkylating agent which is an y-electrophilic equivalent of ethyl 3-oxobutyrate [6].The alkylated compounds 3a, b were obtained in high yields from 2 and the 2-0x0cycloalkane-1-carbonitriles la, b [7] under the conditions of phase-transfer catalysis (Bu,NHSO,/CH2CI2/2~ aq. NaOH; Scheme 1 ). Deprotection of the enol-ether function in 3a, b with CF,COOH provided the desired P-keto esters 4a and 4b in 92 and 94% yield, respectively').All attempts to convert 4a or 4b into a ring-enlarged compound under different conditions (LiN(i-Pr),An analogous alkylation of/?-keto esters with methyl 4-bromo-3-methoxy-2-butenoate and Na sand in Et,O, followed by deprotection with CF,COOH was already described [8].

Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E

“…While simply stated, however, our requisite nitrile-containing all carbon-quaternary center was viewed as challenging to fashion as a single enantiomer given literature precedent. Indeed, both the Hesse 22 and Herzon 23 groups have shown that under basic conditions these centers in similar rings can both eliminate and/or racemize. Moreover, asymmetric methods to install such nitrile groups directly in a 1,4-fashion are arguably lacking; 24 for example, as shown in Scheme 6 a recent asymmetric synthesis from the Qin group 25 relied instead upon a −CH 2 OPiv group as a surrogate for such a cyanide, with substantive functional group changes needed to reach the desired material.…”